Combination immune checkpoint inhibition for older patients with oesophageal squamous cell cancer
Authors: Harriet C Baker, Elizabeth C Smyth
Journal: The Lancet Healthy Longevity (2022)

Oesophageal squamous cell cancer is a common disease globally and one of the leading causes of cancer mortality worldwide.1Sung H Ferlay J Siegel RL et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (17955) Google Scholar The highest incidence of oesophageal squamous cell cancer is in patients aged 65 years and older, who are underrepresented in clinical trials that define standards of care.2Cancer Research UKCancer statistics.https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/oesophageal-cancer/incidence#heading-OneDate: 2022Date accessed: May 12, 2022Google Scholar Consequently, extrapolating results from registration trials to the general older population could lead to unexpected efficacy and toxicity outcomes.Oesophageal squamous cell cancer is often diagnosed when the cancer is not suitable for curative surgery and, sadly, for these patients survival is usually less than 18 months.3Kato K Sun J Shah M et al.Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study.Lancet. 2021; 398: 759-771Summary Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 4Doki Y Ajani JA Kato K et al.Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.N Engl J Med. 2022; 386: 449-462Crossref PubMed Scopus (70) Google Scholar Following progression of cancer on first-line chemotherapy, immune checkpoint inhibition is the recommended standard of care based on the results of several randomised clinical trials.5Kato K Cho BC Takahashi M et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Summary Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 6Shen L Kato K Kim SB et al.Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase iii study.J Clin Oncol. 2022; (published online April 20.)https://doi.org/10.1200/JCO.21.01926Google Scholar, 7Lordick F Mariette C Haustermans K Obermannová R Arnold D Oesophageal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27: v50-v57Summary Full Text Full Text PDF PubMed Scopus (572) Google Scholar Subgroup analysis of the ATTRACTION-3 trial,5Kato K Cho BC Takahashi M et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Summary Full Text Full Text PDF PubMed Scopus (438) Google Scholar which compared nivolumab with chemotherapy in second-line treatment of oesophageal squamous cell cancer, suggested that patients aged 65 years or older did not have the same magnitude of benefit from nivolumab as patients younger than 65 years, meaning that investigating nivolumab specifically in older patients and intensifying treatment beyond nivolumab monotherapy is justified.In The Lancet Healthy Longevity, Matthias Ebert and colleagues8Ebert MP Meindl-Beinker NM Gutting T et al.Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA): a multicentre, open-label phase 2 trial.Lancet Health Longevity. 2022; 3: e417-e427Summary Full Text Full Text PDF Scopus (1) Google Scholar describe the results of the RAMONA trial, which investigated the immune checkpoint inhibitors nivolumab and ipilimumab in patients aged 65 years or older with advanced oesophageal squamous cell cancer that had already progressed on first-line systemic chemotherapy. Patients in RAMONA were initially treated with nivolumab alone once every 2 weeks for three cycles to facilitate early diagnosis of toxicity associated with checkpoint inhibition. Patients without safety concerns at 6 weeks then had ipilimumab added to their treatment. Ebert and colleagues found that 44 (67%) of 66 patients were safely treated with nivolumab and could therefore proceed to doublet immune checkpoint inhibitor therapy. Across patients treated with nivolumab monotherapy and patients treated with the ipilimumab nivolumab doublet, the overall response rate to treatment was 18·2% (95% CI 9·8–29·6), which is in line with the overall response rate observed for nivolumab in the ATTRACTION-3 trial and for tislelizumab in the RATIONALE 302 trial. Previous findings from the CheckMate 648 trial4Doki Y Ajani JA Kato K et al.Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.N Engl J Med. 2022; 386: 449-462Crossref PubMed Scopus (70) Google Scholar showed that the combination of nivolumab and ipilimumab was associated with a higher overall response rate, compared with chemotherapy (in patients with a PD-L1 status of >1%). The response rate of nivolumab with or without ipilimumab was notably lower than 35% in the RAMONA trial, suggesting that the ipilimumab nivolumab doublet therapy might not augment response to the same degree as it does in the younger cohort of patients from CheckMate 648. However, this effect is challenging to accurately assess without a randomised control or parsing of outcomes according to treatment group.4Doki Y Ajani JA Kato K et al.Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.N Engl J Med. 2022; 386: 449-462Crossref PubMed Scopus (70) Google Scholar Similarly, duration of response and median overall survival were lower in RAMONA than in global randomised trials, which is likely to reflect the older age of the population.5Kato K Cho BC Takahashi M et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Summary Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 6Shen L Kato K Kim SB et al.Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase iii study.J Clin Oncol. 2022; (published online April 20.)https://doi.org/10.1200/JCO.21.01926Google Scholar Although adding ipilimumab to nivolumab was associated with improved survival outcomes in RAMONA, this finding could be due to a bias in selecting an immunotherapy-tolerant group of patients for ipilimumab treatment after the safety run-in, rather than any effect of ipilimumab specifically in older patients.It is understandably challenging to conduct clinical trials using toxic anticancer drugs in older people because of the higher prevalence of frailty and multiple comorbidities in this population. As a result, the patients in RAMONA will have likely been on the fitter end of the spectrum to have been deemed eligible for the study. Despite this careful patient selection and admirable pre-treatment comprehensive geriatric assessment, toxicity was shown, highlighting the vulnerability of older adults. Serious adverse events (which might be life-threatening or require hospitalisation) occurred in 45 (68%) of 66 patients. This finding could reflect the older age of participants in the trial but could also relate to the high rate of tobacco-related and alcohol-related comorbidities often observed in patients with oesophageal squamous cell cancer.9Pandeya N Olsen CM Whiteman DC Sex differences in the proportion of esophageal squamous cell carcinoma cases attributable to tobacco smoking and alcohol consumption.Cancer Epidemiol. 2013; 37: 579-584Crossref PubMed Scopus (53) Google Scholar Interestingly, although adding ipilimumab to nivolumab is usually associated with increased toxicity, this did not appear to be the case in RAMONA, indicating that selecting patients who are tolerant to nivolumab before instituting ipilimumab could result in lower toxicity in general.The translational research included in RAMONA is comprehensive but exploratory given the small size of study. Interestingly, digital analysis of histopathology images stained with haematoxylin and eosin showed that haematoxylin and eosin were able to predict PD-L1 status with some accuracy, which could be useful in upscaling PD-L1 testing on a wider scale. Several genes were also found to be of interest on transcriptomic analysis of peripheral blood mononuclear cells, which requires validation in independent datasets. This work could be expanded further to identify significant biomarkers to benefit patients of all ages.The RAMONA trial shows the efficacy and safety of checkpoint inhibition as a second-line therapy for selected older patients with advanced oesophageal squamous cell cancer. However, as patients can now receive combination nivolumab-ipilimumab in first-line therapy following the results of CheckMate 648, new treatment combinations targeting resistance biomarkers might be more attractive. As novel targets come into development, an approach such as that of the RAMONA trial that characterises the efficacy of these treatments in older populations could be valuable. Oesophageal squamous cell cancer is a common disease globally and one of the leading causes of cancer mortality worldwide.1Sung H Ferlay J Siegel RL et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (17955) Google Scholar The highest incidence of oesophageal squamous cell cancer is in patients aged 65 years and older, who are underrepresented in clinical trials that define standards of care.2Cancer Research UKCancer statistics.https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/oesophageal-cancer/incidence#heading-OneDate: 2022Date accessed: May 12, 2022Google Scholar Consequently, extrapolating results from registration trials to the general older population could lead to unexpected efficacy and toxicity outcomes. Oesophageal squamous cell cancer is often diagnosed when the cancer is not suitable for curative surgery and, sadly, for these patients survival is usually less than 18 months.3Kato K Sun J Shah M et al.Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study.Lancet. 2021; 398: 759-771Summary Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 4Doki Y Ajani JA Kato K et al.Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.N Engl J Med. 2022; 386: 449-462Crossref PubMed Scopus (70) Google Scholar Following progression of cancer on first-line chemotherapy, immune checkpoint inhibition is the recommended standard of care based on the results of several randomised clinical trials.5Kato K Cho BC Takahashi M et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Summary Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 6Shen L Kato K Kim SB et al.Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase iii study.J Clin Oncol. 2022; (published online April 20.)https://doi.org/10.1200/JCO.21.01926Google Scholar, 7Lordick F Mariette C Haustermans K Obermannová R Arnold D Oesophageal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27: v50-v57Summary Full Text Full Text PDF PubMed Scopus (572) Google Scholar Subgroup analysis of the ATTRACTION-3 trial,5Kato K Cho BC Takahashi M et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Summary Full Text Full Text PDF PubMed Scopus (438) Google Scholar which compared nivolumab with chemotherapy in second-line treatment of oesophageal squamous cell cancer, suggested that patients aged 65 years or older did not have the same magnitude of benefit from nivolumab as patients younger than 65 years, meaning that investigating nivolumab specifically in older patients and intensifying treatment beyond nivolumab monotherapy is justified. In The Lancet Healthy Longevity, Matthias Ebert and colleagues8Ebert MP Meindl-Beinker NM Gutting T et al.Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA): a multicentre, open-label phase 2 trial.Lancet Health Longevity. 2022; 3: e417-e427Summary Full Text Full Text PDF Scopus (1) Google Scholar describe the results of the RAMONA trial, which investigated the immune checkpoint inhibitors nivolumab and ipilimumab in patients aged 65 years or older with advanced oesophageal squamous cell cancer that had already progressed on first-line systemic chemotherapy. Patients in RAMONA were initially treated with nivolumab alone once every 2 weeks for three cycles to facilitate early diagnosis of toxicity associated with checkpoint inhibition. Patients without safety concerns at 6 weeks then had ipilimumab added to their treatment. Ebert and colleagues found that 44 (67%) of 66 patients were safely treated with nivolumab and could therefore proceed to doublet immune checkpoint inhibitor therapy. Across patients treated with nivolumab monotherapy and patients treated with the ipilimumab nivolumab doublet, the overall response rate to treatment was 18·2% (95% CI 9·8–29·6), which is in line with the overall response rate observed for nivolumab in the ATTRACTION-3 trial and for tislelizumab in the RATIONALE 302 trial. Previous findings from the CheckMate 648 trial4Doki Y Ajani JA Kato K et al.Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.N Engl J Med. 2022; 386: 449-462Crossref PubMed Scopus (70) Google Scholar showed that the combination of nivolumab and ipilimumab was associated with a higher overall response rate, compared with chemotherapy (in patients with a PD-L1 status of >1%). The response rate of nivolumab with or without ipilimumab was notably lower than 35% in the RAMONA trial, suggesting that the ipilimumab nivolumab doublet therapy might not augment response to the same degree as it does in the younger cohort of patients from CheckMate 648. However, this effect is challenging to accurately assess without a randomised control or parsing of outcomes according to treatment group.4Doki Y Ajani JA Kato K et al.Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma.N Engl J Med. 2022; 386: 449-462Crossref PubMed Scopus (70) Google Scholar Similarly, duration of response and median overall survival were lower in RAMONA than in global randomised trials, which is likely to reflect the older age of the population.5Kato K Cho BC Takahashi M et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Summary Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 6Shen L Kato K Kim SB et al.Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase iii study.J Clin Oncol. 2022; (published online April 20.)https://doi.org/10.1200/JCO.21.01926Google Scholar Although adding ipilimumab to nivolumab was associated with improved survival outcomes in RAMONA, this finding could be due to a bias in selecting an immunotherapy-tolerant group of patients for ipilimumab treatment after the safety run-in, rather than any effect of ipilimumab specifically in older patients. It is understandably challenging to conduct clinical trials using toxic anticancer drugs in older people because of the higher prevalence of frailty and multiple comorbidities in this population. As a result, the patients in RAMONA will have likely been on the fitter end of the spectrum to have been deemed eligible for the study. Despite this careful patient selection and admirable pre-treatment comprehensive geriatric assessment, toxicity was shown, highlighting the vulnerability of older adults. Serious adverse events (which might be life-threatening or require hospitalisation) occurred in 45 (68%) of 66 patients. This finding could reflect the older age of participants in the trial but could also relate to the high rate of tobacco-related and alcohol-related comorbidities often observed in patients with oesophageal squamous cell cancer.9Pandeya N Olsen CM Whiteman DC Sex differences in the proportion of esophageal squamous cell carcinoma cases attributable to tobacco smoking and alcohol consumption.Cancer Epidemiol. 2013; 37: 579-584Crossref PubMed Scopus (53) Google Scholar Interestingly, although adding ipilimumab to nivolumab is usually associated with increased toxicity, this did not appear to be the case in RAMONA, indicating that selecting patients who are tolerant to nivolumab before instituting ipilimumab could result in lower toxicity in general. The translational research included in RAMONA is comprehensive but exploratory given the small size of study. Interestingly, digital analysis of histopathology images stained with haematoxylin and eosin showed that haematoxylin and eosin were able to predict PD-L1 status with some accuracy, which could be useful in upscaling PD-L1 testing on a wider scale. Several genes were also found to be of interest on transcriptomic analysis of peripheral blood mononuclear cells, which requires validation in independent datasets. This work could be expanded further to identify significant biomarkers to benefit patients of all ages. The RAMONA trial shows the efficacy and safety of checkpoint inhibition as a second-line therapy for selected older patients with advanced oesophageal squamous cell cancer. However, as patients can now receive combination nivolumab-ipilimumab in first-line therapy following the results of CheckMate 648, new treatment combinations targeting resistance biomarkers might be more attractive. As novel targets come into development, an approach such as that of the RAMONA trial that characterises the efficacy of these treatments in older populations could be valuable. HCB declares travel support from Servier. ECS declares consulting fees, travel support, and honoraria for lectures from Amal Therapeutics, Amgen, Astellas, AstraZeneca, Beigene, Bristol Myers Squibb, Daiichi Sankyo, Imedex, Merck, Novartis, Pfizer, Roche, Servier, and Zymeworks. Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA): a multicentre, open-label phase 2 trialPatients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment. Full-Text PDF Open Access